Auto-Regulation of Leptin Neurobiology

Abstract

The clinical use of the hormone leptin, a key regulator of food intake, to treat the most common instances of obesity has so far failed. In this issue, Zhao et al. (2019) report that, paradoxically, reducing leptin levels in obese mice increases their sensitivity to the concentrations that remain, and leads to reductions in weight gain, thus suggesting why these earlier trials may have failed and possibly a new approach to treating obesity.

Figure 1.. Valence of Physiological Responses to Changes in Ambient Leptin Is Dependent on the Relationship of the New Concentration to Cellular Desensitization Threshold

There is a level of circulating leptin, above which the mouse or human hypothalamus (and probably other brain regions) is desensitized. This threshold is determined by concurrent metabolic circumstance (related to adiposity) and probably by developmental and genetic factors, as well as cell-type specificities. In the lean state, adding a small amount of leptin does not raise the concentration above the threshold, so weight is lost; adding a large amount of leptin raises concentrations above the desensitization threshold: the axis becomes insensitive and weight is gained. If the individual is sufficiently obese, the leptin threshold may be exceeded so that the organism is desensitized to additional leptin. Withdrawing leptin in the lean state leads to weight gain. In the obese state, partially withdrawing leptin restores sensitivity to ambient leptin and leads to weight loss. In both states, complete withdrawal leads to weight gain. This contextual dependence accounts for the apparently paradoxical effects on energy intake and expenditure of raising or lowering ambient leptin in obese or lean individuals.